The landscape of epilepsy-related GATOR1 variants

Abstract

A full list of authors and affiliations appears at the end of the paper.Purpose: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway Methods:We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants.Results: The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drugresistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign.Conclusion: Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.Genetics in Medicine (2018) https://doi

Inclusion of hemimegalencephaly into the phenotypic spectrum of NPRL3 pathogenic variants in familial focal epilepsy with variable foci

“…Genetic investigation revealed a partial 38-kb deletion comprising eight exons (exons [8][9][10][11][12][13][14][15] and the 3′UTR of the NPRL3 gene in Family I, and a novel nonsense variant c.1063C>T, p.Gln355* in NPRL3 in Family II. Genetic investigation revealed a partial 38-kb deletion comprising eight exons (exons [8][9][10][11][12][13][14][15] and the 3′UTR of the NPRL3 gene in Family I, and a novel nonsense variant c.1063C>T, p.Gln355* in NPRL3 in Family II.…”

“…Genetic investigation revealed a partial 38-kb deletion comprising eight exons (exons [8][9][10][11][12][13][14][15] and the 3′UTR of the NPRL3 gene in Family I, and a novel nonsense variant c.1063C>T, p.Gln355* in NPRL3 in Family II. 9,12,13 The two families further corroborate the phenotypic spectrum of the NPRL3 gene and showed a remarkable phenotypic variability ranging from severe medication-refractory epilepsy associated with developmental delay to mild epilepsy and infrequent seizures. 9,12,13 The two families further corroborate the phenotypic spectrum of the NPRL3 gene and showed a remarkable phenotypic variability ranging from severe medication-refractory epilepsy associated with developmental delay to mild epilepsy and infrequent seizures.…”

“…Whole-exome sequencing and single nucleotide polymorphism array analysis revealed pathogenic variants in NPRL3 in each family, a partial ~38-kb deletion encompassing eight exons (exons [8][9][10][11][12][13][14][15] In 2013, the disheveled, Egl-10, and pleckstrin domaincontaining protein 5 (DEPDC5) gene was identified as the first culprit gene for FFEVF. 3,5 DEPDC5 is a component of GATOR1 complex (GAP activity toward Rags), a complex of three proteins (DEPDC5, NPRL2, and NPRL3) that negatively regulates the amino acid-sensing branch of the mTORC1 pathway.…”

“…7 DEPDC5 germline mutations have been reported in a variety of focal epilepsy phenotypes, from nonlesional focal epilepsies to malformation-accompanying focal epilepsy syndromes including hemimegalencephaly. 9,10 An increasing number of presumably pathogenic variants in the coding region of the NPRL3 gene have so far been reported in sporadic and familial cases of focal epilepsies with or without focal cortical dysplasia, [9][10][11][12][13] including two partial deletions in the NPRL3 gene. 9,10 An increasing number of presumably pathogenic variants in the coding region of the NPRL3 gene have so far been reported in sporadic and familial cases of focal epilepsies with or without focal cortical dysplasia, [9][10][11][12][13] including two partial deletions in the NPRL3 gene.…”

“…8 Recently, emphasis on the contribution of the GATOR1 complex proteins to the pathogenesis of FFEVF has been further supported by the identification of germline mutations in the other two GATOR1 complex genes, the nitrogen permease regulator like-2 and 3 (NPRL2 and NPRL3) genes, in families with FFEVF. 9,10 An increasing number of presumably pathogenic variants in the coding region of the NPRL3 gene have so far been reported in sporadic and familial cases of focal epilepsies with or without focal cortical dysplasia, [9][10][11][12][13] including two partial deletions in the NPRL3 gene. 13 Herein, we expand the phenotypic spectrum associated with NPRL3 pathogenic variants by describing two multiplex families with FFEVF in whom molecular analysis revealed two truncating variants in NPRL3.…”